tbuckley/cabot-search huggingface dataset:
CNSC-33. MOLECULAR AND FUNCTIONAL DRIVERS OF ACTIVITY DEPENDENT GLIOBLASTOMA PROLIFERATION
Authors: Mikias Negussie, Saritha Krishna, Ying Wei, Alexander Aabedi, Vardhaan Ambati, Andy Daniel, Katie Lu, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma, the most common primary brain tumor in adults, is a major cause of neurological morbidity and mortality with no effective therapies. Its proliferation and invasion are regulated by direct and paracrine-mediated neuronal activity. In this study, we uncover molecular targets and protein-protein signaling driving activity dependent proliferation. To identify candidate molecular pathways, we used high-density electrode arrays in vivo to record human local field potentials. Single-cell RNA sequencing identified Netrin-G1 (NTNG1) and thrombospondin-1 (TSP1) elevation in glioblastoma clonal population that proliferates in response to the presence of neurons. The amino acid sequence of NTNG1 and the TSR1 domain of TSP1 were utilized to predict the 3D interaction surface of NTNG1 and TSP1. Compared to structure predictions of NTNG1 and its known binding partner NGL1, NTNG1 and TSP1 complex predictions showed agreement between machine learning predicted models and lower predicted aligned error in interdomain regions of the complex, suggesting higher confidence in the relative position of NTNG1-TSP1 as compared to NTNG1-NGL1. We performed 45 protein structure predictions and two molecular dynamics simulations of mutant and WT TSP1 in complex with NTNG1. Each simulation box consisted of &amp;gt;263,000 atoms, each run for 50 million 2 femtosecond timesteps for a total simulation time of 200 ns. These calculations confirmed a stable complex in the WT condition and significant conformational change in the R46A condition, emphasizing the importance of this residue in mediating NTNG1-TSP1 binding. Computational affinity models between NTNG1 and TSP1 were validated by pull-down assays and immunofluorescence labelling using cerebral organoid and human glioma-neuronal coculture models. Finally, we design small molecule and fusion-protein inhibitors disrupting this interaction. Here we advance the development of targeted precision-medicine therapies to treat glioblastoma proliferation through activity-dependent mechanisms.
CTNI-21. PHASE I STUDY OF BTK INHIBITOR IBRUTINIB WITH TEMOZOLOMIDE AND RADIATION IN NEWLY-DIAGNOSED GLIOBLASTOMA (EQUILIBRIUM): FINAL TRIAL REPORT
Authors: Manmeet Ahluwalia, Ahmad Ozair, Atulya Khosla, Neha Patel, Paul Elson, Erin Murphy, Samuel Chao, John Suh, Glen Stevens, David Peereboom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma carries dismal prognosis for which novel therapeutics are urgently needed. Ibrutinib, an oral small molecule inhibitor of BTK, has been shown in preclinical models to inhibit cancer stem cells in glioblastoma. We sought to investigate safety and tolerability of ibrutinib for newly-diagnosed glioblastoma (nGBM). METHODS EQUILIBRIUM was a prospective, phase I trial conducted in nGBM patients with KPS ≥ 70% and normal organ function. Patients received standard of care chemoradiation plus ibrutinib in a 3 + 3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60Gy over 6 weeks with/without 75 mg/m2 of temozolomide (TMZ) in MGMT methylated and unmethylated cohorts respectively. Secondary objective was to determine safety, overall survival (OS), and progression-free survival. RESULTS 26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib+RT arm. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ in methylated arm. In Ibrutinib+RT+TMZ arm, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). Median OS for MGMT methylated arm was 26.0 (22.0-NA) months and for MGMT unmethylated cohort was 14.0 (8.54-NA) months. Median OS for EGFR-amplified was 29.5 (21.9-NA) months and for EGFR-non-amplified was 21.8 (16.6-NA) months. 2-year OS for MGMT methylated arm was 56% (34-95%) and for MGMT unmethylated arm was 2% (6-70%). CONCLUSIONS 420 mg of Ibrutinib daily is safe and feasible with TMZ and RT for nGBM. Ibrutinib appears promising compared to historical outcomes in MGMT methylated patients. EGFR-amplified patients potentially derive significant benefit. Trial information: NCT03535350.
NCOG-39. DOSE-EFFECT RELATIONSHIP OF DEXAMETHASONE ON OUTCOMES OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Jessica White, Lauren Webb, Bryan Neth, Ugur Sener, Rafid Mustafa
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Dexamethasone is commonly used for symptomatic management in primary central nervous lymphoma (PCNSL). The optimal dosing scheme for dexamethasone is unknown and practice patterns widely vary among clinicians. In this study, we explored the dose-effect relationship of dexamethasone on PCNSL outcomes to better influence quality care for these patients. METHODS We retrospectively identified 24 Mayo Clinic patients (1/1/2018 – 12/31/2022) with pathologically confirmed PCNSL who received dexamethasone. All patients otherwise received standard oncologic care including methotrexate-based systemic chemotherapy and/or radiotherapy. The association between dexamethasone dosing regimens and clinical outcomes (performance status, clinical and radiographic response, survival) in addition to potential adverse effects were evaluated in the acute phase of presentation and at first post-treatment oncology follow up. RESULTS Nine patients received less frequent dexamethasone dosing (4 mg twice daily or less), while 15 received more frequent dexamethasone dosing (4 mg four times daily). Fourteen patients received dexamethasone prior to biopsy, 2 of which (1 in each cohort) had a non-diagnostic biopsy and required a second procedure 3 weeks to 3 months later to confirm PCNSL diagnosis. There were no statistically significant differences in time to diagnosis from presentation or clinical and radiographic improvement including Karnofsky Performance Status, reduction in seizures, or survival between the two cohorts. Additionally, there were no differences in the frequency of adverse events (e.g., hyperglycemia, hypertension, infection, psychosis) between the two dosing regimens. CONCLUSIONS These results suggest that more frequent dexamethasone dosing is not associated with better clinical outcomes in the symptomatic management of PCNSL. Twice daily or less frequent dosing can be considered without compromising patient outcomes.
INNV-20. PREDICTING RESPONSE TO CHEMOTHERAPY IN HIGH GRADE GLIOMAS USING <i>EX VIVO</i> 3D CELL CULTURE FUNCTIONAL PRECISION ONCOLOGY PLATFORM – A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Maciej Mrugala, Maya Hrachova, Wendy Sherman, Shannon Fortin Ensign, Mylan Blomquist, Alyx Porter, Tracy Thompson, DeNia Greene, Panos Anastasiadis, George Vasmatzis, Wan-Hsin Lin, Ian Dunn, Alfredo Quiñones-Hinojosa, Richard Zimmerman, Kristin Swanson, Bernard Bendok
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treatment of high-grade glioma (HGG) remains a challenge. Several groups have developed ex vivo drug sensitivity assays to evaluate susceptibility of the tumor tissue to specific chemotherapeutics. This tool, in addition to molecular analysis of tumors might provide another layer of confidence in choosing treatments for patients with high-grade gliomas. METHODS 3D PredictTM platform (Kiyatec, Greenville, SC, USA) was tested at three academic medical centers in the United States. Twelve patients with newly diagnosed and recurrent HGGs were included. Tumor spheroids created ex vivo were exposed to twelve pre-selected drugs. Responses were reported as: no response, moderate response and response. We analyzed: demographics, histopathology, stage of disease, success rate and results of the ex vivo assay and clinical implications. RESULTS Majority of patients were women (67%). Median age was 58.5. Histology: GBM-83%, HGGs-17%. Eighty three percent of the samples represented recurrent disease. Sixty percent represented first recurrence while the remaining 40% represented 2nd or 3rd recurrence. Eight out of 12 tissue samples (67%) were successfully tested ex vivo. In six cases (75%), the information was used for immediate clinical decision making. In 2 cases, the decision was deferred until the next progression of the disease. The drugs chosen for treatment based on assay results included: olaparib (the assay was positive for response to rucaparib), temozolomide, lomustine, carboplatin and irinotecan. CONCLUSIONS This platform is easy to use in a standard clinical setting, the success rate for creating viable spheroids for drug sensitivity testing is high and the information obtained can be useful in clinical practice. Addition of other agents to the assay, correlation with molecular testing of the tumor tissue and attempt to assess response to drug combinations should be considered in further development of this technology. Prospective clinical trial is needed to validate this approach for routine clinical use.
BIOM-45. GLIOMA CSF PROTEOMICS FOR PHARMACODYNAMIC BIOMARKER AND THERAPEUTIC TARGET DISCOVERY
Authors: Cecile Riviere-Cazaux, Lucas Carlstrom, Amanda Munoz-Casabella, Kari Andersen, Samar Ikram, Arthur Warrington, Terry Burns
Journal: Neuro-Oncology (2023)

Abstract Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatment course toward our goal of identifying CSF-derived biomarkers of treatment response. CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic. Fold-changes for each protein were calculated between different timepoints and ranked for each comparison of interest. Treatment with pembrolizumab alone results in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x), suggesting potential for combination with multiple agents. Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF-A (7.32x), VEGF-B (2.21x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF. In conclusion, the global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.
EXTH-79. A NOVEL ANTI-GALECTIN-3 ANTIBODY THERAPEUTIC SYNERGIZES WITH TEMOZOLOMIDE IN PRECLINICAL MODELS TO DIMINISH TUMOR GROWTH, DECREASE MIGRATION, AND PROLONG SURVIVAL
Authors: Anne Marie Barrette, Krutika Deshpande, Bailey McDonald, Marvin Cadiente, Xi Wang, Dongxu Sun
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive, invasive, and malignant primary brain cancer whose standard of care for nearly 20 years has been surgical resection followed by radiotherapy and temozolomide (TMZ) treatment, resulting in a median survival of 15 months following diagnosis. Heterogenous tumor cell populations that evade resection and develop chemoradiation resistance highlight the need for novel therapies that can target both the migratory and proliferative nature of GBM cells. Galectin-3, a carbohydrate-binding protein overexpressed in the GBM parenchyma and stromal astrocytes, is a potent modulator of cell proliferation, migration, angiogenesis, T-cell inhibition, and M2 macrophage polarization, and is seen to increase following TMZ and radiation treatment. Heightened Galectin-3 expression levels correlate to lower survival in glioma patients, thus greatly underscoring the need for targeting Galectin-3 in conjunction with initial standard-of-care treatment. Here, we characterize the therapeutic effects of a brain-penetrant monoclonal anti-Galectin-3 antibody (Gal3 Ab) we have developed for its ability to inhibit GBM growth and migration in several in vitro assays and in vivo heterotopic and orthotopic mouse models. Our Gal3 Ab significantly decreases cell viability, neurosphere migration, and cell invasion in vitro in the presence of full length or truncated Gal3, whose expression and secretion in GBM cells is enhanced following short and long-term TMZ stimulation. We find that Galectin-3 directly binds to EGFR, amplified in ~40% of GBM patients, as well as its most commonly mutated form, EGFRvIII, and our Gal3 Ab can block these bindings, decrease EGFR activation, and alter EGFR localization. In vivo, our Gal3 Ab decreases tumor burden and improves survival in combination with temozolomide, compared to standard-of-care treatment alone in multiple cell-line models. Our pre-clinical studies highlight the potential for our novel Gal3 antibody to further improve TMZ efficacy and benefit GBM patients by diminishing tumor cell migration and slowing tumor growth.
BIOM-26. RAPID IDENTIFICATION OF <i>IDH1</i>-R132 VARIANTS IN GLIOMA WITH LOCKED NUCLEIC ACID LOOP-MEDIATED ISOTHERMAL AMPLIFICATION (LNA-LAMP)
Authors: Kristian Choate, Edward Raack, Veronica Line, Matthew Jennings, Robert Belton, Robert Winn, Paul Mann
Journal: Neuro-Oncology (2023)

Abstract Point mutations that impact the catalytic site of isocitrate dehydrogenase 1 (IDH1) are associated with an extended overall survival of approximately 3.8 years for glioma patients compared to 1 year for those with wild-type IDH1. The difference in survival benefit is associated with the maximal surgical resection of IDH1 mutant tumors, making intraoperative knowledge of the mutational status valuable. Unfortunately, current methods used to determine IDH1-R132 mutational status are incompatible with obtaining real-time results. We have developed a panel of assays that use LNA-LAMP to identify commonly encountered IDH1-R132 variants (R132H, R132C, R132G, R132S, R132L) within 40 minutes. These assays require little preanalytical processing, no complex equipment, and yield results which are easily interpreted by the naked eye. Tumor samples are initially subjected to a 5-minute alkaline digest, then added directly to LNA-LAMP reactions containing primers unique to each IDH1-R132 variant. Discrimination between the wild-type and mutant allele is achieved with the integration of locked nucleic acids within primers. A reaction with an IDH1-R132R specific primer serves as the sample positive control, as all tumor lysates are expected to contain wild-type IDH1 DNA. Lysates are incubated for 35 minutes in a hot water bath, followed by visual interpretation using a pH-based colorimetric indicator, where samples positive for the mutation appear a vibrant yellow while those lacking the mutation remain pink. This method has been rigorously tested with patient-derived tumor lysates, yielding reproducible and accurate results, and has an analytical sensitivity of about 20% mutant DNA in a background of wild-type DNA. This sensitivity is comparable to that of Sanger Sequencing while simultaneously offering a more cost-effective and efficient workflow. LNA-LAMP is amenable for use in the intraoperative window to allow patients with an IDH1-R132 mutation the benefit of a maximal surgical resection.
NIMG-38. TUMOR VOLUME GROWTH RATES AND DOUBLING TIMES DURING ACTIVE SURVEILLANCE OF IDH-MUTANT LOW-GRADE GLIOMA
Authors: Ankush Bhatia, Raquel Moreno, Anne Reiner, Subhiksha Nandakumar, Henry Walch, Teena Thomas, Philip Nicklin, Clara Choi, Anna Skakodub, Rachna Malani, Vivek Prabhakaran, Pallavi Tiwari, Maria Diaz, Katherine Panageas, Ingo Mellinghoff, Tejus Bale, Robert Young
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Isocitrate-dehydrogenase-mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on magnetic resonance imaging may act as an earlier measure of clinical benefit during the active surveillance period. METHODS We integrated 3-dimensional volumetric measurements with clinical, radiological, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics. RESULTS Using log-linear mixed modeling, the entire cohort (n=128) had a continuous %TVGR per 6 months of 10.46% (95% CI: [9.11%, 11.83%]) and a doubling time of 3.5 years (95% CI: [3.10-3.98]). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI: [15.57%, 22.89%]) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI: [7.32%, 11.80%]) (P &amp;lt; 0.0001). Using joint modeling to co-model the longitudinal course of TVGR and overall survival, we found each unit increase in log volume resulted in more than a 3-fold increase in risk of death (HR=3.83, 95% CI: [2.32-6.30], P &amp;lt; 0.0001). CONCLUSIONS TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.
SURG-39. EVALUATING THE EFFECTIVENESS OF NON-NAVIGATED 2D INTRAOPERATIVE ULTRASOUND IN GLIOMA SURGERY: RECONSIDERING THE PUSH FOR MORE COMPLEX INTRAOPERATIVE IMAGING
Authors: Santiago Cepeda, Sergio García-García, Ignacio Arrese, Rosario Sarabia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION In the swiftly evolving domain of neurosurgical technology, conventional methodologies like the non-navigated two-dimensional intraoperative ultrasound (nn-2D-IOUS) might be at risk of being overlooked. This research investigates the clinical effectiveness and surgical significance of nn-2D-IOUS, particularly for glioma removal procedures. METHODS This retrospective research, conducted at a single healthcare institution, reviewed 99 unselected patients diagnosed with both high and low-grade gliomas. The main objective was to examine the competency of nn-2D-IOUS in delivering satisfactory image quality, recognizing leftover tumor tissue, and its impact on the extent of tumor removal. Early postoperative MRI data were used as a reliable comparison measure to verify these findings. RESULTS nn-2D-IOUS exhibited notable efficiency, generating superior image quality in nearly 79% of analyzed cases. It showcased a sensitivity of 68% and a remarkable specificity of 100%, thus affirming its instrumental role in intraoperative tumor identification. In scenarios where complete tumor excision was intended, a resection surpassing 95% of the original tumor volume was accomplished in 86% of patients. Moreover, when the nn-2D-IOUS didn't detect residual tumor, the average volume of overlooked tumor tissue was significantly small, approximately 0.27 cm³. CONCLUSION Our research presents persuasive evidence emphasizing the critical role and effectiveness of nn-2D-IOUS in glioma surgeries. The findings underline the potential of leveraging cost-efficient, traditional technologies like nn-2D-IOUS to attain superior surgical results, even when compared to more sophisticated alternatives. This understanding has profound implications, especially for resource-limited environments, underscoring the need to maximize the usage of available tools to enhance patient care in a practical, economical manner.
BIOM-10. KI-67 IS ASSOCIATED WITH PROGRESSION-FREE SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Drew Bergman, Sumyuktha Anand, Gobind Gill, Brent Harris, Camilo Fadul, Matthew Havrda, Kelli Pointer
Journal: Neuro-Oncology (2023)

Abstract Identifying predictive and prognostic markers for glioblastoma (GBM) is an area of intense investigation. The objective of this study was to evaluate OLIG2 and Ki-67 as prognostic biomarkers. A tissue microarray with clinical data was created for 70 patients diagnosed with GBM between 2002-2007 at a single institution. Immunohistochemistry was performed to evaluate expression of OLIG2 and Ki-67. Overall survival and progression free survival (PFS) were calculated using the Kaplan-Meier method. Univariable (UVA) and multivariable (MVA) analysis was performed using Cox proportional hazards modeling. The median age of diagnosis was 63, 66% of patients were male, 80% had a KPS ≥70, 64% had a subtotal resection or biopsy, and 36% had a gross total resection. Median OS and PFS were 13.3 months and 9.5 months respectively. For patients who received resection plus chemoradiation, median OS and PFS were 16.7 months and 9.5 months respectively. 36.4% of patient samples had Ki-67 expression fraction &amp;gt; 20%. 18.0% had heavy OLIG2 staining. On MVA, lower KPS was associated with shorter OS and radiation therapy was associated with longer OS. OLIG2 was not associated with OS or PFS. Patients who had a Ki-67 &amp;lt; 20% had a shorter PFS, but not OS on MVA. Our data demonstrate higher Ki-67 levels correlate with improved PFS without an OS benefit. This association persisted for patients receiving standard of care treatment. OLIG2 levels did not correlate with PFS or OS in either cohort. Our study indicates that further investigation is needed to determine whether Ki-67 is useful in predicting recurrence risk and potentially changing treatment strategies for these patients, as well as the mechanism behind the associated improvement seen with higher Ki-67 levels. These data are currently limited by lack of IDH and MGMT status but suggest Ki-67 should be further investigated as a biomarker for progression.